Aqueous oral pharmaceutical suspension compositions

ABSTRACT

Provided is an aqueous oral pharmaceutical suspension composition comprising vamorolone Form I. Also provided are methods for its preparation and its use.

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 62/815,097 filed Mar. 7, 2019, thedisclosure of which is incorporated by reference in its entirety for allpurposes.

Vamorolone is a synthetic glucocorticoid corticosteroid, also known asVB-15, VBP-15, 16α-methyl-9,11-dehydroprednisolone, or17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione:

Pre-clinical data have shown that vamorolone binds potently to theglucocorticoid receptor and has anti-inflammatory effects similar totraditional glucocorticoid drugs. Testing of multiple mouse models ofinflammatory states has shown efficacy similar to prednisolone, anddramatically improves side effect profiles, including loss of growthstunting and loss of bone fragility.

Provided is an aqueous oral pharmaceutical suspension compositioncomprising vamorolone Form I. Also provided is an aqueous oralpharmaceutical suspension composition comprising: vamorolone Form I; atleast one suspending agent; and at least one suspension vehicle. Alsoprovided are methods for preparing such suspensions as well as methodsfor their use in methods of treating or reducing the symptoms ofmuscular dystrophy.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a pXRD pattern of vamorolone Form I.

FIG. 2 shows a TGA profile of vamorolone Form I.

FIG. 3 shows a DSC profile of vamorolone Form I.

FIG. 4 shows a flow diagram for the manufacturing process used to makethe aqueous oral pharmaceutical suspension composition comprisingvamorolone Form I described in Example 3.

FIG. 5 shows a flow diagram for the manufacturing process used to makethe aqueous oral pharmaceutical suspension composition comprisingvamorolone Form I described in Example 4.

DETAILED DESCRIPTION

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

VAMOROLONE: As used herein, “vamorolone” refers to17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione (alsoknown as VBP15) and has the structure:

POLYMORPHS AND POLYMORPHIC FORMS: Vamorolone can exist as variouspolymorphic forms. As used herein, the terms, “polymorphs” and“polymorphic forms” and related terms herein refer to crystalline formsof the same molecule, and different polymorphs may have differentphysical properties such as, for example, melting temperatures, heats offusion, solubilities, dissolution rates and/or vibrational spectra as aresult of the arrangement or conformation of the molecules in thecrystal lattice. The differences in physical properties exhibited bypolymorphs affect pharmaceutical parameters such as storage stability,compressibility and density (important in formulation and productmanufacturing), and dissolution rates (an important factor inbioavailability). Differences in stability can also result from changesin chemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical property (e.g., tabletscrumble on storage as a kinetically favored polymorph converts tothermodynamically more stable polymorph) or both (e.g., tablets of onepolymorph are more susceptible to breakdown at high humidity). As aresult of solubility/dissolution differences, in the extreme case, somepolymorphic transitions may result in lack of potency or, at the otherextreme, toxicity. In addition, the physical properties of the crystalmay be important in processing, for example, one polymorph might be morelikely to form solvates or might be difficult to filter and wash free ofimpurities (i.e., particle shape and size distribution might bedifferent between polymorphs).

Polymorphs of a molecule can be obtained by a number of methods, asknown in the art. Such methods include, but are not limited to, meltrecrystallization, melt cooling, solvent recrystallization, desolvation,rapid evaporation, rapid cooling, slow cooling, vapor diffusion andsublimation.

Techniques for characterizing polymorphs include, but are not limitedto, differential scanning calorimetry (DSC), X-ray powder diffractometry(XRPD), single crystal X-ray diffractometry, vibrational spectroscopy,e.g., IR and Raman spectroscopy, solid state NMR, hot stage opticalmicroscopy, scanning electron microscopy (SEM), electron crystallographyand quantitative analysis, particle size analysis (PSA), surface areaanalysis, solubility studies and dissolution studies.

To “characterize” a solid form of a compound, one may, for example,collect XRPD data on solid forms of the compound and compare the XRPDpeaks of the forms. For example, when only three solid forms, e.g.,Forms X and Y and Material N, are compared and the Form X pattern showsa peak at an angle where no peaks appear in the Form Y or Material Npattern, then that peak, for that compound, distinguishes Form X fromForm Y and Material N and further acts to characterize Form X. Thecollection of peaks which distinguish e.g., Form X from the other knownforms is a collection of peaks which may be used to characterize Form X.Those of ordinary skill in the art will recognize that there are oftenmultiple ways, including multiple ways using the same analyticaltechnique, to characterize solid forms. Additional peaks could also beused, but are not necessary, to characterize the form up to andincluding an entire diffraction pattern. Although all the peaks withinan entire XRPD pattern may be used to characterize such a form, a subsetof that data may, and typically is, used to characterize the form.

An XRPD pattern is an x-y graph with diffraction angle (typically ° 2θ)on the x-axis and intensity on the y-axis. The peaks within this patternmay be used to characterize a crystalline solid form. As with any datameasurement, there is variability in XRPD data. The data are oftenrepresented solely by the diffraction angle of the peaks rather thanincluding the intensity of the peaks because peak intensity can beparticularly sensitive to sample preparation (for example, particlesize, moisture content, solvent content, and preferred orientationeffects influence the sensitivity), so samples of the same materialprepared under different conditions may yield slightly differentpatterns; this variability is usually greater than the variability indiffraction angles. Diffraction angle variability may also be sensitiveto sample preparation. Other sources of variability come from instrumentparameters and processing of the raw X-ray data: different X-rayinstruments operate using different parameters and these may lead toslightly different XRPD patterns from the same solid form, and similarlydifferent software packages process X-ray data differently and this alsoleads to variability. These and other sources of variability are knownto those of ordinary skill in the pharmaceutical arts. Due to suchsources of variability, it is usual to assign a variability of ±0.2°2θto diffraction angles in XRPD patterns.

ABOUT: As used herein, the term “about” is intended to qualify thenumerical values which it modifies, denoting such a value as variablewithin a margin of error. When no particular margin of error, such as astandard deviation to a mean value given in a chart or table of data, isrecited, the term “about” should be understood to mean that range whichwould encompass the recited value and the range which would be includedby rounding up or down to that figure as well, taking into accountsignificant figures.

ADMINISTERING: As used herein, “administering” means to provide acompound or other therapy, remedy, or treatment such that an individualinternalizes a compound.

DISEASE: As used herein, the term “disease” is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the human or animal body or of one of its parts thatimpairs normal functioning, is typically manifested by distinguishingsigns and symptoms, and causes the human or animal to have a reducedduration or quality of life.

IN NEED OF TREATMENT and IN NEED THEREOF: As used herein, “in need oftreatment” and “in need thereof” when referring to treatment are usedinterchangeably to mean a judgment made by a caregiver (e.g. physician,nurse, nurse practitioner, etc. in the case of humans; veterinarian inthe case of animals, including non-human mammals) that an individual oranimal requires or will benefit from treatment. This judgment is madebased on a variety of factors that are in the realm of a caregiver'sexpertise, but that includes the knowledge that the individual or animalis ill, or will become ill, as the result of a disease, condition ordisorder that is treatable by the compounds of the invention.Accordingly, the compounds of the invention can be used in a protectiveor preventive manner; or compounds of the invention can be used toalleviate, inhibit or ameliorate the disease, condition or disorder.

NF-κB-MEDIATED DISEASE: As used herein, the term “NF-κB-mediateddisease” refers to a disease having a significant and pathologicinflammatory component that can be addressed by inhibition of NF-κB. Thedisease may be completely or partially mediated by modulating theactivity or amount of NF-κB. In particular, the disease is one in whichmodulation of NF-κB results in some effect on the underlying diseasee.g., administration of a NF-κB modulator results in some improvement inat least some of the patients being treated. The term “NF-κB-mediateddisease” also refers to the following diseases, even though thecompounds disclosed herein exert their effects through biologicalpathways and/or processes other than NF-κB: muscular dystrophy,arthritis, traumatic brain injury, spinal cord injury, sepsis, rheumaticdisease, cancer atherosclerosis, type 1 diabetes, type 2 diabetes,leptospiriosis renal disease, glaucoma, retinal disease, ageing,headache, pain, complex regional pain syndrome, cardiac hypertrophy,muscle wasting, catabolic disorders, obesity, fetal growth retardation,hypercholesterolemia, heart disease, chronic heart failure,ischemia/reperfusion, stroke, cerebral aneurysm, angina pectoris,pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonaryhypertension, asthma, chronic obstructive pulmonary disease, Sjogren'ssyndrome, hyaline membrane disease, kidney disease, glomerular disease,alcoholic liver disease, gut diseases, peritoneal endometriosis, skindiseases, nasal sinusitis, mesothelioma, anhidrotic ecodermaldysplasia-ID, behcet's disease, incontinentia pigmenti, tuberculosis,asthma, crohn's disease, colitis, ocular allergy, appendicitis, paget'sdisease, pancreatitis, periodonitis, endometriosis, inflammatory boweldisease, inflammatory lung disease, silica-induced diseases, sleepapnea, AIDS, HIV-1, autoimmune diseases, antiphospholipid syndrome,lupus, lupus nephritis, familial mediterranean fever, hereditaryperiodic fever syndrome, psychosocial stress diseases, neuropathologicaldiseases, familial amyloidotic polyneuropathy, inflammatory neuropathy,parkinson's disease, multiple sclerosis, alzheimer's disease, amyotropiclateral sclerosis, huntington's disease, cataracts, and hearing loss.

PHARMACEUTICAL COMPOSITION: As used here, “pharmaceutical composition”means a composition comprising at least one active ingredient, such asvamorolone or a polymorphic form thereof, whereby the composition isamenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

PURE: As used herein, the term “pure” means about 90-100%, preferably95-100%, more preferably 98-100% (wt/wt) or 99-100% (wt/wt) purecompound; e.g. less than about 10%, less than about 5%, less than about2% or less than about 1% impurity is present. Such impurities include,e.g., degradation products, oxidized products, epimers, solvents, and/orother undesirable impurities.

RANGES: When ranges of values are disclosed, and the notation “from n₁ .. . to n₂” is used, where n₁ and n₂ are the numbers, then unlessotherwise specified, this notation is intended to include the numbersthemselves and the range between them. This range may be integral orcontinuous between and including the end values. By way of example, therange “from 2 to 6 carbons” is intended to include two, three, four,five, and six carbons, since carbons come in integer units. Compare, byway of example, the range “from 1 to 3 μM (micromolar),” which isintended to include 1 μM, 3 μM, and everything in between to any numberof significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

ROOM TEMPERATURE: As used herein, the term “room temperature” refers toa temperature of 68 to 86 F.

STABLE: As used herein, the term “stable” refers to both chemical(shelf-life) and physical stability (suspension uniformity). Improveduniformity results in an improved product because less shaking of thesuspension is required before dosing and allows the product to be storedlonger (i.e. longer shelf-life) because the drug in the product will notsettle and compact.

SUSPENSION: As used herein, the term “suspension” refers to a mixture ofa solid in liquid. In contrast, an “emulsion” refers to a mixture of twoimmiscible liquids.

THERAPEUTICALLY ACCEPTABLE: As used herein, the term “therapeuticallyacceptable” refers to those compounds (or salts, prodrugs, tautomers,zwitterionic forms, etc.) suitable for use in contact with the tissuesof patients without undue toxicity, irritation, and allergic response,are commensurate with a reasonable benefit/risk ratio, and are effectivefor their intended use.

THERAPEUTICALLY EFFECTIVE: As used herein, the phrase “therapeuticallyeffective” is intended to qualify the amount of active ingredients usedin the treatment of a disease or disorder. This amount will achieve thegoal of reducing or eliminating the disease or disorder.

TREATMENT: As used herein, “treating,” “treatment,” and the like meansameliorating a disease so as to reduce or eliminate its cause, itsprogression, its severity, or one or more of its symptoms, or otherwisebeneficially alter the disease in a subject. Treatment may also bepreemptive in nature, i.e., it may include prophylaxis of disease in asubject exposed to or at risk for the disease. Prevention of a diseasemay involve complete protection from disease, for example as in the caseof prevention of infection with a pathogen, or may involve prevention ofdisease progression, for example from prediabetes to diabetes. Forexample, prevention of a disease may not mean complete foreclosure ofany effect related to the diseases at any level, but instead may meanprevention of the symptoms of a disease to a clinically significant ordetectable level. Prevention of diseases may also mean prevention ofprogression of a disease to a later stage of the disease.

Throughout this specification, unless the context requires otherwise,the word “comprise”, or variations such as “comprises” or “comprising”will be understood to imply the inclusion of a stated step or element orinteger or group of steps or elements or integers but not the exclusionof any other step or element or integer or group of elements orintegers.

Throughout this specification, unless specifically stated otherwise orthe context requires otherwise, reference to a single step, compositionof matter, group of steps, or group of compositions of matter shall betaken to encompass one and a plurality (i.e. one or more) of thosesteps, compositions of matter, groups of steps, or groups ofcompositions of matter.

Each embodiment described herein is to be applied mutatis mutandis toeach and every other embodiment unless specifically stated otherwise.

Those skilled in the art will appreciate that the invention(s) describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the invention(s)includes all such variations and modifications. The invention(s) alsoincludes all of the steps, features, compositions and compounds referredto or indicated in this specification, individually or collectively, andany and all combinations or any two or more of steps or features unlessspecifically stated otherwise.

The present invention(s) is not to be limited in scope by the specificembodiments described herein, which are intended for the purpose ofexemplification only. Functionally-equivalent products, compositions,and methods are clearly within the scope of the invention(s), asdescribed herein.

It is appreciated that certain features of the invention(s), which are,for clarity, described in the context of separate embodiments, can alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the invention(s), which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

Aqueous Oral Pharmaceutical Suspension

Provided is an aqueous oral pharmaceutical suspension compositioncomprising vamorolone Form I. Also provided is an aqueous oralpharmaceutical suspension composition comprising: vamorolone Form I; atleast one suspending agent; and at least one suspension vehicle.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises vamorolone Form I in an amount of between about 2%and about 10% w/w. In some embodiments, the aqueous oral pharmaceuticalsuspension composition comprises vamorolone Form I in an amount ofbetween about 2% and about 9% w/w. In some embodiments, the aqueous oralpharmaceutical suspension composition comprises vamorolone Form I in anamount of between about 2% and about 8% w/w. In some embodiments, theaqueous oral pharmaceutical suspension composition comprises vamoroloneForm I in an amount of between about 2% and about 7% w/w. In someembodiments, the aqueous oral pharmaceutical suspension compositioncomprises vamorolone Form I in an amount of between about 3% and about5% w/w. In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises vamorolone Form I in an amount of about 4% w/w.

In some embodiments, vamorolone Form I is characterized by an X-raypowder diffraction pattern comprising peaks, in terms of ° 2θ, at about11.9, about 13.7, about 16.1, and about 18.3 with radiation Cu Kα. Insome embodiments, vamorolone Form I is characterized by an X-ray powderdiffraction pattern comprising peaks, in terms of ° 2θ, at about 11.9,about 13.7, about 14.4, about 14.8, about 16.1, about 17.0, and about18.3 with radiation Cu Kα. In some embodiments, vamorolone Form I ischaracterized by an X-ray powder diffraction pattern substantially asshown in FIG. 1.

In some embodiments, vamorolone Form I is characterized by athermogravimetric analysis profile showing less than about 0.5% weightloss below about 175° C. In some embodiments, vamorolone Form I ischaracterized by a thermogravimetric analysis profile substantially asshown in FIG. 2.

In some embodiments, vamorolone Form I is characterized by an exothermicevent onset at 180.7° C. and a melting event with an onset and peaktemperatures of 231.0° C. and 234.7° C., respectively, as measured bydifferential scanning calorimetry. In some embodiments, vamorolone FormI is characterized by a differential scanning calorimetry tracesubstantially as shown in FIG. 3.

In some embodiments, vamorolone Form I has a chemical purity of at leastabout 95%, at least about 96%, at least about 97%, at least about 98%,at least about 99%, or at least about 99.5% by high performance liquidchromatography. In some embodiments, vamorolone Form I has totalchemical impurities of not more than about 0.5%, not more than about0.4%, not more than about 0.3%, not more than about 0.2%, or not morethan about 0.1%, by high performance liquid chromatography.

In some embodiments, vamorolone Form I has a particle size such that d₉₀is less than about 50 am, less than about 40 am, or less than about 30am. In some embodiments, vamorolone Form I has a particle size such thatd₅₀ is less than about 30 am, less than about 20 am, between about 10and about 20 am, or between about 14 and about 17 am. In someembodiments, vamorolone Form I has a particle size such that d₅₀ is lessthan about 20 am, less than about 10 am, between about 5 and about 10am, or between about 5 and about 6.5 m.

In some embodiments, the suspending agent is chosen from acacia, agar,alginic acid or a salt thereof, bentonite, carbomers,carboxymethylcellulose or a salt thereof, carrageenan, corn starch,ethylcellulose, gelatin, guar gum, hydroxyethylcellulose,hydroxyethylmethylcellulose, hydroxypropyl cellulose,hydroxypropylmethylcellulose, methylcellulose, microcrystallinecellulose, pectin, polyvinyl alcohol, polyvinyl pyrrolidone,polyethylene oxide, colloidal silicon dioxide, tragacanth, xanthan gum,and mixtures thereof.

In some embodiments, the suspending agent is chosen fromcarboxymethylcellulose or a salt thereof, microcrystalline cellulose,xanthan gum, and mixtures thereof.

In some embodiments, the suspending agent comprises a mixture ofmicrocrystalline cellulose, xanthan gum, and carboxymethylcellulose, ora salt thereof.

In some embodiments, the suspending agent comprises a mixture ofmicrocrystalline cellulose, xanthan gum, and sodiumcarboxymethylcellulose.

In some embodiments, the at least one suspending agent is present in anamount of between about 0.1% to about 5% w/w, such as between about 0.1%to about 0.5% w/w, for example, between about 0.2% to about 0.4% w/w. Incertain embodiments, the at least one suspending agent comprises xanthangum present in the amount of between about 0.2% and about 0.4%.

In some embodiments, the at least one suspending agent is present in anamount of between about 0.5% to about 5% w/w, such as between about 0.5%to about 4% w/w, for example, between about 1% to about 3% w/w.

In some embodiments, the suspension vehicle is chosen from a sweetener(e.g. a sugar, sugar substitute, or sugar alcohol) or low molecularweight polyol. In some embodiments, the suspension vehicle is chosenfrom xylitol, propylene glycol, glycerin, sorbitol, liquid glucose,dextrose, and mixtures thereof. In some embodiments, the suspensionvehicle is propylene glycol, dextrose, or a mixture thereof. In someembodiments, the suspension vehicle is a mixture of propylene glycol anddextrose.

In some embodiments, the suspension vehicle is present in an amount ofbetween about 0.1% to about 10% w/w. In some embodiments, the suspensionvehicle is present in an amount of between about 3% to about 10% w/w. Insome embodiments, the suspension vehicle is present in an amount ofbetween about 4% to about 8% w/w. In some embodiments, the suspensionvehicle is present in an amount of between about 5% to about 7% w/w. Insome embodiments, the suspension vehicle is present in an amount ofabout 6% w/w.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition further comprises at least one surfactant. In someembodiments, the surfactant is chosen from an alkyl aryl polyetherpolymer, a polyoxyethylene polyoxypropylene polymer, polysorbates,polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40stearates, sorbitan monolaureates, poloxamer and combinations thereof.In some embodiments, the surfactant is a polysorbate. In someembodiments, the surfactant is polysorbate 80.

In some embodiments, the surfactant is present in amount of betweenabout 0.01% to about 1% w/w. In some embodiments, the surfactant ispresent in an amount of between about 0.01% to about 0.5% w/w. In someembodiments, the surfactant is present in an amount of between about0.05% to about 0.2% w/w. In some embodiments, the surfactant is presentin an amount of about 0.1% w/w.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition further comprises at least one preservative. In someembodiments, the preservative is chosen from benzethonium chloride,phenyl ethanol, phenyl propanol, phenyl mercuric acetate, phenylmercuric nitrate, phenyl mercuric borate, chlorhexidine acetate orgluconate, cetrimide, chlorocresol, sodium methyl paraben, methylparaben, sodium propyl paraben, thimerosal, sodium benzoate,benzalkonium chloride, potassium sorbate, and mixtures thereof. In someembodiments, the preservative is methylparaben, sodium benzoate, or amixture thereof. In some embodiments, the preservative is a mixture ofmethylparaben and sodium benzoate.

In some embodiments, the at least one preservative is present in anamount of between about 0.1% and about 1% w/w. In some embodiments, theat least one preservative is present in an amount of between about 0.1%and about 0.5% w/w. In some embodiments, the at least one preservativeis present in an amount of about 1% w/w. In some embodiments, the atleast one preservative is present in an amount of about 0.1% w/w. Insome embodiments, the at least one preservative is present in an amountof about 0.2% w/w.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition further comprises at least one stabilizing agent. In someembodiments, the stabilizing agent is ethylenediaminetetraacetic acid(EDTA).

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition further comprises a buffer. In some embodiments, the bufferis sufficient to neutralize the suspension to a pH of about 4 and 5. Insome embodiments, the buffer is sufficient to neutralize the suspensionto a pH of about 4.5 and 5.5. In some embodiments, the buffer issufficient to neutralize the suspension to a pH of about 4. In someembodiments, the buffer is sufficient to neutralize the suspension to apH of about 5.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition further comprises a flavoring agent. As vamorolone has afairly neutral taste, as opposed to prednisolone which tastes bitter,the addition of a flavoring agent is useful to make the suspension evenmore palatable.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises between 3.6% and 4.4% w/w vamorolone Form I,between 0.4% and 0.6% w/w sodium carboxymethyl cellulose, between 0.1%and 2% w/w xanthan gum, between 0.8% and 1.2% w/w dextrose, between0.05% and 0.15% w/w polysorbate 80, between 1.7% and 2.7% w/wmicrocrystalline cellulose, between 0.1% and 0.3% w/w dibasic sodiumphosphate, between 0.1% and 0.3% w/w citric acid, between 0.05% and0.15% w/w methylparaben, between 0.05% and 0.15% w/w sodium benzoate,between 4% and 6% w/w glycerin, between 0.05% and 0.15% w/w flavoring,and between 83% and 89% w/w water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises about 4% w/w vamorolone Form I, about 0.5% w/wsodium carboxymethyl cellulose, about 0.15% w/w xanthan gum, about 1.0w/w % dextrose, about 0.1% w/w polysorbate 80, about 2.2% w/wmicrocrystalline cellulose, about 0.2% w/w dibasic sodium phosphate,about 0.2% w/w citric acid, about 0.1% w/w methylparaben, about 0.1% w/wsodium benzoate, about 5% w/w glycerin, about 0.1% w/w flavoring, andabout 86.4% w/w water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises between 3.6% and 4.4% w/w vamorolone Form I,between 0.4% and 0.6% w/w sodium carboxymethyl cellulose, between 0.1%and 2% w/w xanthan gum, between 0.8% and 1.2% w/w dextrose, between0.05% and 0.15% w/w polysorbate 80, between 0.5% and 0.8% w/wmicrocrystalline cellulose, between 0.1% and 0.3% w/w dibasic sodiumphosphate, between 0.1% and 0.3% w/w citric acid, between 0.05% and0.15% w/w methylparaben, between 0.05% and 0.15% w/w sodium benzoate,between 4% and 6% w/w propylene glycol, between 0.05% and 0.15% w/wflavoring, and between 83% and 89% w/w water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises about 4% w/w vamorolone Form I, about 0.5% w/wsodium carboxymethyl cellulose, about 0.15% w/w xanthan gum, about 1.0%w/w dextrose, about 0.1% w/w polysorbate 80, about 0.6% w/wmicrocrystalline cellulose, about 0.2% w/w dibasic sodium phosphate,about 0.2% w/w citric acid, about 0.1% w/w methylparaben, about 0.1% w/wsodium benzoate, about 5% w/w propylene glycol, about 0.1% w/wflavoring, and about 86.4% w/w water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises 3-5% w/w vamorolone Form I, 2-3% w/w dextrose,0.1-0.2% w/w carboxymethyl cellulose, 1-1.5% microcrystalline cellulose,0.2-0.4% w/w dibasic sodium phosphate, 0.1-0.3% w/w citric acid,0.4-0.6% w/w sodium benzoate, 0.1-0.3% w/w potassium sorbate, 0.05-0.2%w/w EDTA, 4-6% w/w glycerin, 0.05-0.2% w/w flavoring, and the remainderwater.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises about 4% w/w vamorolone Form I, about 1% w/wdextrose, about 0.05% w/w carboxymethyl cellulose (e.g., about 0.045%w/w high viscosity), about 1.2% microcrystalline cellulose, about 0.3%w/w dibasic sodium phosphate (e.g., about 0.28% w/w), about 0.2% w/wcitric acid (e.g. about 0.21% w/w), about 0.5% w/w sodium benzoate,about 0.2% w/w potassium sorbate, about 0.1% w/w EDTA, about 5% w/wglycerin, about 0.1% w/w flavoring, and the remainder water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises 3-5% w/w vamorolone Form I, 0.05-0.2% w/wsucralose, 0.2-0.4% w/w xanthan gum, 0.2-0.4% w/w dibasic sodiumphosphate, 0.1-0.3% w/w citric acid, 0.4-0.6% w/w sodium benzoate,0.1-0.3% w/w potassium sorbate, 0.05-0.2% w/w EDTA, 4-6% w/w glycerin,about 0.05-0.2% w/w flavoring, and the remainder water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises about 4% w/w vamorolone Form I, about 0.1% w/wsucralose, about 0.3% w/w xanthan gum, about 0.3% w/w dibasic sodiumphosphate (e.g., about 0.28% w/w), about 0.2% w/w citric acid (e.g.about 0.21% w/w), about 0.5% w/w sodium benzoate, about 0.2% w/wpotassium sorbate, about 0.1% w/w EDTA, about 5% w/w glycerin, about0.1% w/w flavoring, and the remainder water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises 3-5% w/w vamorolone Form I, 0.05-0.2% w/wsucralose, 0.2-0.4% w/w xanthan gum, 0.2-0.4% w/w dibasic sodiumphosphate, 0.1-0.3% w/w citric acid, 0.05% w/w-0.3% w/w sodium benzoate,4-6% w/w glycerin, 0.05-0.2% w/w flavoring, and the remainder water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises about 4% w/w vamorolone Form I, about 0.1% w/wsucralose, about 0.3% w/w xanthan gum, about 0.3% w/w dibasic sodiumphosphate (e.g., about 0.28% w/w), about 0.2% w/w citric acid (e.g.about 0.21% w/w), about 0.2% w/w-0.1% w/w sodium benzoate, about 5% w/wglycerin, about 0.1% w/w flavoring, and the remainder water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises 3-5% w/w vamorolone Form I, 2-3% w/w dextrose,0.1-1% w/w carboxymethyl cellulose, 0.1-0.2% w/w xanthan gum, 1-1.5%microcrystalline cellulose, 0.1-0.3% w/w dibasic sodium phosphate,0.1-0.3% w/w citric acid, 0.05-0.3% methylparaben, 0.1-0.3% w/w sodiumbenzoate, 4-6% w/w glycerin, 0.05-0.2% w/w flavoring, and the remainderwater.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprises about 4% w/w vamorolone Form I, about 1% w/wdextrose, about 0.5% w/w carboxymethyl cellulose, about 0.15% w/wxanthan gum, about 1.2% microcrystalline cellulose, about 0.2% w/wdibasic sodium phosphate (e.g., about 0.19% w/w), about 0.2% w/w citricacid (e.g. about 0.19% w/w), about 0.1% methylparaben, about 0.2% w/wsodium benzoate, about 5.0% w/w glycerin, about 0.1% w/w flavoring, andthe remainder water.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprising vamorolone Form I exhibits extended shelf lifestability. The shelf life may be up to about six months, twelve months,eighteen months, twenty-four months, thirty months, or thirty-sixmonths.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprising vamorolone Form I is stable at 25° C./60%relative humidity for at least three months, at least four months, atleast five months, at least six months, at least seven months, at leasteight months, at least nine months, at least ten months, at least elevenmonths, at least one year, or at least two years.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprising vamorolone Form I has total chemical impuritiesof not more than about 2%, not more than about 1.5%, not more than about1%, not more than about 0.9%, not more than about 0.8%, not more thanabout 0.7%, not more than about 0.6%, or not more than about 0.55%, byhigh performance liquid chromatography.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprising vamorolone Form I has not more than about 0.5%,not more than about 0.4%, not more than about 0.3%, not more than about0.2%, or not more than about 0.1%, by high performance liquidchromatography of any individual impurity.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprising vamorolone Form I has not more than about 0.5%,not more than about 0.4%, not more than about 0.3%, not more than about0.2%, or not more than about 0.1%, by high performance liquidchromatography of an epoxide having the formula:

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprising vamorolone Form I has not more than about 0.5%,not more than about 0.4%, not more than about 0.3%, not more than about0.2%, or not more than about 0.15%, by high performance liquidchromatography of a ketone having the formula:

The ketone impurity is also referred to as the impurity having arelative retention time of 1.27-1.28.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprising vamorolone Form I has not more than about 0.5%,not more than about 0.4%, not more than about 0.3%, not more than about0.2%, or not more than about 0.16%, by high performance liquidchromatography of a diastereomeric compound having the formula:

The ketone impurity is also referred to as the impurity having arelative retention time of 1.05.

In some embodiments, the aqueous oral pharmaceutical suspensioncomposition comprising vamorolone Form I has not more than about 0.5%,not more than about 0.4%, or not more than about 0.3%, by highperformance liquid chromatography of an acetate having the formula:

The acetate impurity is also referred to as the impurity having arelative retention time of 1.38-1.40.Methods of Use

Also provided are methods for treating a disease having a significantand pathologic inflammatory component that can be addressed byinhibition of NF-κB in a human or animal subject in need of suchtreatment comprising administering to the subject an amount of asuspension described herein effective to reduce or prevent the diseasein the subject, optionally in combination with at least one additionalagent for the treating the disease that is known in the art.

Specific diseases to be treated by the compounds, compositions, andmethods disclosed herein include acid-induced lung injury, acne (PAPA),acute respiratory distress syndrome, ageing, AIDS, HIV-1, alcoholichepatitis, alcoholic liver disease, allergic bronchpulmonayaspergillosis, Alzheimer's disease, amyotropic lateral sclerosis, anginapectoris, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis,antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis,asthma, allergen induced asthma, non-allergen induced asthma,atherosclerosis, atopic dermatitis, autoimmune diseases, Behcet'sdisease, Bell's palsy, Blau syndrome, bronchiolitis, cancer, cardiachypertrophy, catabolic disorders, cataracts, cerebral aneurysm, chronicheart failure, chronic lung disease (including of prematurity), chronicobstructive pulmonary disease, colitis, ulcerative colitis, complexregional pain syndrome, connective tissue diseases, crohn's disease,cryopyrin-associated periodic syndromes, cyrptococcosis, cysticfibrosis, deficiency of the interleukin-1-receptor antagonist (DIRA),dermatitis, dermatomyositis, endometriosis, endotoxemia, familialamyloidotic polyneuropathy, familial cold urticaria, familialmediterranean fever, fetal growth retardation, glaucoma, glomerulardisease, glomerular nephritis, gut diseases, head injury, headache,hearing loss, heart disease, Henoch-Scholein purpura, hepatitis,hereditary periodic fever syndrome, herpes zoster and simplex,Huntington's disease, hyaline membrane disease, hypercholesterolemia,hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplastic andother anemias, incontinentia pigmenti, infectious mononucleosis,inflammatory bowel disease, inflammatory lung disease, inflammatoryneuropathy, inflammatory pain, irritant-induced inflammation, plantirritant-induced inflammation, poison ivy/urushiol oil-inducedinflammation, chemical irritant-induced inflammation, bee sting-inducedinflammation, insect bite-induced inflammation, ischemia/reperfusion,kidney disease, kidney injury caused by parasitic infections,leptospiriosis, leukemia, lung injury, lupus, lupus nephritis, lymphoma,meningitis, mesothelioma, Muckle-Wells syndrome (urticaria deafnessamyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy,mycosis fungoides, myelodysplastic syndrome, myocarditis, myositis,nasal sinusitis, necrotizing enterocolitis, neonatal onset multisysteminflammatory disease (NOMID), nephrotic syndrome, neuritis,neuropathological diseases, obesity, ocular allergy, osteoarthritis,otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease,pericarditis, periodic fever, periodonitis, peritoneal endometriosis,pertussis, pharyngitis and adenitis (PFAPA syndrome), pneumosystisinfection, polyarteritis nodosa, polycystic kidney disease,polymyositis, psoriasis, psychosocial stress diseases, pulmonarydisease, pulmonary fibrosis, pulmonary hypertension, pyodermagangrenosum, pyogenic sterile arthritis, renal disease, retinal disease,rheumatic disease, rheumatoid arthritis, sarcoidosis, sebborrhea,sepsis, silica-induced diseases, Sjogren's syndrome, skin diseases,sleep apnea, solid tumors, spinal cord injury, stroke, subarachnoidhemorrhage, sunburn, burns, thrombocytopenia, TNF receptor associatedperiodic syndrome (TRAPS), toxoplasmosistransplant, organ transplant,tissue transplant, traumatic brain injury, tuberculosis, type 1diabetes, type 2 diabetes, uveitis.

In some embodiments, the disease is chosen from acute lymphocyticleukemia, Addison's disease, adrenal hyperplasia, adrenocorticalinsufficiency, allergic conjunctivitis, alopecia, amyloidosis,angioedema, anterior segment inflammation, autoimmune hepatitis,Behcet's syndrome, berylliosis, bone pain, bursitis, carpal tunnelsyndrome, chorioretinitis, chronic lymphocytic leukemia, corneal ulcer,diffuse intrinsic pontine glioma, epicondylitis, erythroblastopenia,gout, gouty arthritis, graft-versus-host disease, hemolytic anemia,Hodgkin's disease, hypercalcemia, hyperammonemia, hypoplastic anemia,idiopathic thrombocytopenic purpura, iritis, juvenile rheumatoidarthritis, keratitis, kidney transplant rejection prophylaxis,Loeffler's syndrome, mixed connective tissue disease, myasthenia gravis,mycosis fungiodes, optic neuritis, pemphigus, pneumonia, pneumonitis,polychondritis, psoriasis, rheumatic carditis, severe pain, sickle cell,sickle cell anemia, Stevens-Johnson syndrome, temporal arteritis,tenosynovitis, thyroiditis, urticarial, Wegener's granulomatosis, andweight loss.

In some embodiments, the disease is asthma or chronic obstructivepulmonary disease

In some embodiments, the disease is Sjogren's syndrome.

In some embodiments, the disease is arthritis.

In some embodiments, the disease is muscular wasting.

In some embodiments, the muscular wasting disease is muscular dystrophy.

In some embodiments, the muscular dystrophy is chosen from Duchennemuscular dystrophy, Becker muscular dystrophy, limb girdle musculardystrophy, congenital muscular dystrophy, facioscapulohumeral musculardystrophy, myotonic muscular dystrophy, oculopharyngeal musculardystrophy, distal muscular dystrophy, and Emery-Dreifuss musculardystrophy.

In some embodiments, the muscular dystrophy is Duchenne musculardystrophy.

In certain embodiments, vamorolone Form I is administered at a dose offrom 0.1 to 500 mg/kg per day. The dose range for adult humans isgenerally from 5 mg to 2 g/day. In some embodiments, the dose range is0.25 to 6.0 mg/kg/day, such as 0.25 mg/kg/day, 0.75 mg/kg/day, 2.0mg/kg/day, or 6.0 mg/kg/day.

For example, provided herein are the following embodiments.

Embodiment 1

An aqueous oral pharmaceutical suspension composition comprising:

vamorolone Form I;

at least one suspending agent; and

at least one suspension vehicle.

Embodiment 2

The suspension of Embodiment 1, comprising vamorolone Form I in anamount of between about 2% and about 10% w/w.

Embodiment 3

The suspension of Embodiment 2, comprising vamorolone Form I in anamount of about 4% w/w.

Embodiment 4

The suspension of any of the preceding Embodiments, wherein thesuspending agent is chosen from acacia, agar, alginic acid or a saltthereof, bentonite, carbomers, carboxymethylcellulose or a salt thereof,carrageenan, corn starch, ethylcellulose, gelatin, guar gum,hydroxyethylcellulose, hydroxyethylmethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,microcrystalline cellulose, pectin, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, colloidal silicon dioxide, tragacanth,xanthan gum, and mixtures thereof (and including salts of any of theforegoing).

Embodiment 5

The suspension of Embodiment 4, wherein the suspending agent is chosenfrom carboxymethylcellulose or a salt thereof, microcrystallinecellulose, xanthan gum, and mixtures thereof.

Embodiment 6

The suspension of Embodiment 4, wherein the suspending agent comprises amixture of microcrystalline cellulose, xanthan gum, andcarboxymethylcellulose, or a salt thereof.

Embodiment 7

The suspension of Embodiment 4, wherein the suspending agent comprises amixture of microcrystalline cellulose, xanthan gum, and sodiumcarboxymethylcellulose.

Embodiment 8

The suspension of any of the preceding Embodiments, wherein the at leastone suspending agent is present in an amount of between about 0.5% toabout 5% w/w.

Embodiment 9

The suspension of any of the preceding Embodiments, wherein thesuspension vehicle is chosen from xylitol, propylene glycol, glycerin,sorbitol, liquid glucose, dextrose, and mixtures thereof.

Embodiment 10

The suspension of Embodiment 9, wherein the suspension vehicle ispropylene glycol, dextrose, or a mixture thereof.

Embodiment 11

The suspension of any one of the preceding Embodiments, wherein thesuspension vehicle is present in an amount of from about 3% to about 10%w/w.

Embodiment 12

The suspension of claim 11, wherein the suspension vehicle comprisesglycerin, the suspension agent comprises xanthan gum, and vamoroloneForm I in an amount of about 4% w/w.

Embodiment 13

The suspension of any of the preceding Embodiments, wherein vamoroloneForm I is further characterized by an X-ray powder diffraction patterncomprising peaks, in terms of ° 2θ, at about 11.9, about 13.7, about16.1, and about 18.3 with radiation Cu Kα.

Embodiment 14

The suspension of any of the preceding Embodiments, wherein vamoroloneForm I is further characterized by an X-ray powder diffraction patternsubstantially as shown in FIG. 1.

Embodiment 15

The suspension of any of the preceding Embodiments, wherein vamoroloneForm I is further characterized by an exothermic event onset at 180.7°C. and a melting event with an onset and peak temperatures of 231.0° C.and 234.7° C., respectively, as measured by differential scanningcalorimetry.

Embodiment 16

The suspension of Embodiment 15, wherein vamorolone Form I is furthercharacterized by a differential scanning calorimetry trace substantiallyas shown in FIG. 3.

Embodiment 17

The suspension of any of the preceding Embodiments, wherein vamoroloneForm I is further characterized by a thermogravimetric analysis profileshowing less than about 0.5% weight loss below about 175° C.

Embodiment 18

The suspension of Embodiment 17, wherein vamorolone Form I is furthercharacterized by a thermogravimetric analysis profile substantially asshown in FIG. 2.

Embodiment 19

The suspension of any one of the preceding Embodiments, wherein thevamorolone Form I has a chemical purity of at least about 95%, at leastabout 96%, at least about 97%, at least about 98%, at least about 99%,or at least about 99.5% by high performance liquid chromatography.

Embodiment 20

The suspension of any one of the preceding Embodiments, wherein thesuspension has total chemical impurities of not more than about 0.6% byhigh performance liquid chromatography.

Embodiment 21

The suspension of any one of the preceding Embodiments, wherein thesuspension has not more than about 0.5% by high performance liquidchromatography of an epoxide having the formula:

Embodiment 22

A method of treating or reducing the symptoms of muscular dystrophy,comprising the administration, to a patient in need thereof, of atherapeutically effective amount of a suspension of any one ofEmbodiments 1 to 20.

Embodiment 23

The method of Embodiment 22, wherein the therapeutically effectiveamount is between 10 mg to 200 mg.

Embodiment 24

The method of Embodiment 22, wherein the therapeutically effectiveamount is between 0.01 mg/kg to 10.0 mg/kg.

Embodiment 25

The method of Embodiment 22, wherein the therapeutically effectiveamount is between 2 mg/kg to 6.0 mg/kg.

Embodiment 26

The method of any one of Embodiments 22 to 25, wherein the musculardystrophy is chosen from Duchenne muscular dystrophy, Becker musculardystrophy, limb girdle muscular dystrophy, congenital musculardystrophy, facioscapulohumeral muscular dystrophy, myotonic musculardystrophy, oculopharyngeal muscular dystrophy, distal musculardystrophy, and Emery-Dreifuss muscular dystrophy.

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein intheir entireties. Where any inconsistencies arise, material literallydisclosed herein controls.

Further embodiments include the embodiments disclosed in the followingExamples, which is not to be construed as limiting in any way.

EXAMPLES

The following examples are included to demonstrate some embodiments ofthe disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples represent techniquesdiscovered by the inventors to function well in the practice of thedisclosure. Those of skill in the art should, however, in light of thepresent disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of thedisclosure, therefore all matter set forth is to be interpreted asillustrative and not in a limiting sense.

Example 1

Compound 2 Preparation

3-TR (100 g, 273 mmol), dichloromethane (DCM, 500 mL) andtetrahydrofuran (THF, 400 mL) were charged to a reaction flask undernitrogen. To this was charged trimethylsilyl imidazole (TMS-imidazole,65.3 g, 466 mmol, 1.7 eq). The resulting mixture was stirred at roomtemperature for 3 hours.

In a separate flask, copper acetate monohydrate (5.4 g, 27 mmol),tetrahydrofuran (400 ml) and1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 53.3 g, 416mmol) were combined and stirred at room temperature for approximately 3hours. The blue mixture was subsequently cooled to −50° C., and to thiswas added methyl magnesium chloride solution (27 ml, 3.0 M in THF, 82mmol) dropwise. After 30 minutes, the mixture had formed a deep blue,sticky “ball.”

The 3-TR/TMS-imidazole mixture was cooled to −50° C. and to this wascharged the copper acetate/DMPU solution above via canula. The residualsticky mass from the copper acetate/DMPU mixture was dissolved using DCM(50 mL) and also transferred.

Methyl magnesium chloride (123.2 mL, 3.0 M solution in THF, 368 mmol)was added dropwise over 45 minutes to the combined reaction mixtures,which were then allowed to stir for 2 hours at −50° C. Subsequent HPLCanalysis showed complete consumption of starting material. The mixturewas allowed to warm to room temperature overnight, with stirring.

Toluene (800 mL) was added to the mixture, followed by 5% acetic acidsolution (600 mL). The aqueous layer was removed and discarded. Theacetic acid wash was repeated. The organic layer was washed with brine(400 mL), 5% sodium bicarbonate solution (400 mL×2), followed by a brinewash (400 mL). The organic solution was dried over sodium sulfate, thenconcentrated to dryness under reduced pressure. The product wasrecovered as a viscous, light golden oil. Mass recovery was 146 grams(119% of theoretical).

Step 2 Compound 3 Preparation

Compound 2 (92 g, 202 mmol) and toluene (1000 mL, 10.9 vol) were chargedto a reaction flask under nitrogen and the solution was cooled to −10°C. A 32 wt % solution of peracetic acid in acetic acid (60 mL, 283 mmol,1.4 eq) was added dropwise over about 30 min maintaining the temperatureat −10° C. The reaction was held for approximately 20 h (HPLC showed 75%Cmpd 3, Cmpd 2 1.5%, 6% diastereomer; 5% epoxide). Starting at −10° C.,a 20% aqueous solution of sodium bisulfite (920 mL, 10 vol) was addedcarefully via addition funnel, keeping the temperature below 10° C.Trifluoroacetic acid (16 mL, 202 mmol, 1 eq) was added and the mixturewas held for 3 h at 0-5° C. to complete desilylation (endpoint by HPLC).The lower aqueous layer was drained, and the organic layer was washedwith a saturated solution of sodium bicarbonate (3×250 mL), followed bywater (1×250 mL), and brine (1×150 mL). The organic layer was then driedover Na₂SO₄, filtered and concentrated to a pasty solid (89 g). Theresidue was taken up in 1.5 vol of EtOAc and transferred to neat heptane(19 vol) to precipitate crude Cmpd 3 as an off-white solid (50 g, 62.5%yield; HPLC 79% Cmpd 3, 5.6% epoxide, 1.7% diastereomer). The crude Cmpd3 (48.5 g) was triturated in hot acetonitrile (2 vol) at 60° C. for 4 h,and then gradually cooled to ambient temperature overnight. The mixturewas filtered using the recycled filtrate to rinse and wash the wet cake.After drying, the recovery was 64.3% (31.2 g; HPLC 93.5% Cmpd 3, 3.3%epoxide). To remove the epoxide impurity, the 31 Cmpd 3 was dissolved inDCM (250 mL, 8 vol) and a solution of 48% HBr in water was added (7.5mL). The mixture was heated at 40° C. for 1 h (HPLC<0.3% epoxide). Themixture was cooled and transferred to a separatory funnel. The loweraqueous layer (brown) was removed and the upper organic layer was washedwith water (200 mL), saturated NaHCO₃ (150 mL), and brine (100 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated to a tanfoam (32 g, ˜100% recovery). Methanol (64 mL, 2 vol) was added to the 32g foam forming a slurry. To this was added a 1:1 solution of MeOH:water(60 mL, 2 vol) dropwise. The slurry cooled to slightly below ambienttemperature and filtered using recycled filtrate to rinse and wash thewet cake. The solids were dried to constant weight, affording 26.1 gCmpd 3 (81% recovery; HPLC 97.8%). The overall yield for Step 2 was32.5%.

Step 3 VBP15 Preparation

Compound 3 (26 g, 65 mmol) and MeOH (156 mL, 6 vol) were mixed in areaction flask and cooled to 0-5° C. A solution of K₂CO₃ (9.9 g, 72mmol, 1.1 eq) in water (65 mL) was added dropwise, and the mixture wasallowed to gradually warm to ambient temperature overnight. Analysis byHPLC showed 2.5% SM and another 5 mol % K₂CO₃ was added and the mixturestirred for another day (HPLC endpoint 1.1% Cmpd 3). The mixture wasneutralized to pH 7 with 1.5 M HCl (53 mL) and ˜25% of the MeOH (30 g)was removed under vacuum to maximize recovery. After stirring for 2days, the product was isolated by filtration using the recycled filtrateto aid transferring the wet cake to the funnel. The wet cake was driedunder vacuum, affording 19.3 g VBP15 (83% yield) as an off-white powder.Analysis of the solids by HPLC showed 98.8% purity with 0.6% Cmpd 3 asthe only major impurity.

Example 2—Preparation of Vamorolone Form I

Power X-Ray Diffraction (pXRD)

The solid samples were examined using X-ray diffractometer (Bruker D8advance). The system is equipped with highly-parallel x-ray beams (GobelMirror) and LynxEye detector. The samples were scanned from 3 to 40°2θ,at a step size 0.02°2θ and a time per step of 19.70 seconds. The tubevoltage and current were 45 kV and 40 mA, respectively. The sample wastransferred from sample container onto zero background XRD-holder andgently ground.

TGA Analysis

TGA analyses were carried out on a TA Instruments TGA Q500.Approximately 2.0 mg of samples was placed in a tared platinum oraluminum pan, automatically weighed, and inserted into the TGA furnace.The samples were heated at a rate of 10° C./min, to final temperature of300° C. The purge gas is nitrogen for balance at 40 ml/min and for thesample at 60 mL/min, respectively.

DSC Analysis

DSC analyses were conducted on a TA Instruments Q200. The calibrationstandard was indium. A sample 2.0 mg in weight was placed into a TA DSCpan, and weight accurately recorded. Crimped pans were used for analysisand the samples were heated under nitrogen (50 ml/min) at a rate of 10°C./min, up to a final temperature of 260° C.

Preparation of Drug Solutions

Drug substance was weighted into glass vials, the vials were then eachfilled with about 5 mL of the desired solvents, stirred (vortex mixer)and heated to 45° C. Residue suspensions consisting of primarily solidparticulates were later used for slurry studies.

Filtration of Drug Solutions/Suspensions

All drug solutions/suspensions were manually filtered into clean glassvials using plastic non-contaminating syringes equipped with 0.22-μmnylon filter cartridges. The filtrates were then used forcrystallization/precipitation studies as outlined below.

Well Plate Preparation/Solvent Distribution/Crystallization

The saturated drug solutions (filtrates) were distributed in a 96-wellplate. The solvents in plate were allowed to evaporate in an operatinglaboratory fume hood under ambient conditions of temperature andhumidity. The plate was covered for the slow solvent evaporation(crystallization) condition. During the process of crystallization, theplate was visually examined and any solid material was analyzed byimaging system, powder x-ray diffraction (PXRD), differential scanningcalorimetry (DSC), and thermogravimetric analysis (TGA), as deemedappropriate based on amount of sample.

The table below lists the solvent(s) from which vamorolone Form I wascrystallized following the parameters in Table 1.

TABLE 1 Solvent 1 Solvent 2 Acetonitrile Acetonitrile AcetonitrileMethanol Acetonitrile THF Acetonitrile Heptane Acetonitrile WaterAcetonitrile Nitromethane Acetone Ethyl acetate Acetone Methanol AcetoneTHF Acetone Toluene Acetone 2-Butanone Acetone Heptane Acetone WaterAcetone Nitromethane ethanol ethanol ethanol Methanol Ethyl acetateToluene Ethyl acetate Heptane Ethyl acetate Nitromethane MethanolMethanol Methanol 2-propanol Methanol THF Methanol Toluene Methanol2-Butanone Methanol dichloromethane Methanol Water Methanol NitromethaneTHF THF THF 2-Butanone THF Heptane THF Nitromethane Toluene 2-ButanoneToluene dichloromethane Toluene Nitromethane 2-Butanone 2-Butanone2-Butanone Heptane dichloromethane Heptane Heptane NitromethaneNitromethane Nitromethane

The crystallized compound was characterized by pXRD (FIG. 1), TGA (FIG.2), and DSC (FIG. 3), which is assigned as Form I. TGA profile showedthat little weight loss was observed prior to decomposition. DSC profileshowed that there is exothermic event, which suggested that phasetransformation/re-crystallization occurred with onset temperature 180.7°C. Then, the crystal solid melted with onset and peak temperatures of231.0 and 234.7° C., respectively, and enthalpy 88.5 J/g.

The drug compound was thermally treated using DSC cell at variousheating rate at 2.0, 5.0, 10.0, 20.0, and 40° C. per minute. The resultsfurther confirmed that recrystallization or phase transformation hasoccurred during the heating process.

A sample, isolated by heating the drug substance in DSC pan to 206° C.and rapidly cooled down, was examined by pXRD, and its pXRD pattern issimilar to the original sample.

Example 3—Preparation of an Aqueous Oral Pharmaceutical SuspensionComposition Comprising Vamorolone Form I

An oral pharmaceutical composition was prepared as a suspension byblending the ingredients in the amounts listed below at Table 2 to forma suspension. FIG. 4 shows a flow diagram for the manufacturing processused to prepare this suspension.

TABLE 2 Ingredient Amount (grams) Vamorolone 4.0 SodiumCarboxymethylcellulose, 0.5 Medium Viscosity, USP Xanthan Gum, NF 0.15Dextrose Anhydrous, USP 1.0 Polysorbate 80, NF 0.1 Avicel CL611Microcrystalline cellulose, NF 2.2 Sodium Phosphate Dibasic, 0.19Anhydrous USP Grade Citric Acid Monohydrate, Granular USP 0.19Methylparaben, Ph. Eur./NF 0.1 Sodium Benzoate NF 0.1 Glycerin, USP 5.0Orange flavor 58.4108.UL PHA 0.1 Sterile Purified Water, USP Qs to 100 *“Qs” denotes the volume of sterile water necessary to bring thecomposition to 100 wt. %.

Example 4—Preparation of an Aqueous Oral Pharmaceutical SuspensionComposition Comprising Vamorolone Form I

An oral pharmaceutical composition was prepared as a suspension byblending the ingredients in the amounts listed below at Table 3 to forma suspension. FIG. 5 shows a flow diagram for the manufacturing processused to prepare this suspension.

TABLE 3 Ingredient Amount (grams) Vamorolone 4.0 Sodium Carboxymethylcellulose, 0.5 Medium Viscosity, USP Xanthan Gum, NF 0.15 DextroseAnhydrous, USP 1.0 Polysorbate 80, NF 0.1 Avicel CL611 Microcrystallinecellulose, NF 0.6 Sodium Phosphate Dibasic, 0.19 Anhydrous USP GradeCitric Acid Monohydrate, Granular USP 0.19 Methylparaben, Ph.Eur./NF 0.1Sodium Benzoate NF 0.1 Propylene Glycol, USP 5.0 Orange flavor58.4108.UL PHA 0.1 Sterile Purified Water, USP Qs to 100

Example 5—Stability Data

Stability results for Vamorolone (Orange) Suspension stored at 5° C. and25° C./60% relative humidity are provided below at Tables 4-6. A HPLCmethod as shown in the table below was used to identify and assay theimpurities.

TABLE 4 Column SiliaChrom ™ dt C₁₈ (150 × 4.6 mm, 3.0 μm)* Mobile PhaseA Water Mobile Phase B Acetonitrile Gradient elution Time (min.) %Mobile Phase B 0 25 15 40 22 100 27 100 32 25 Flow rate 1.5 mL/minColumn 45° C. ± 2° C. Temperature Injection 10 μL Volume Needle and50/50 (v/v) H₂)/Acetonitrile Column Wash Detection UV 240 nm (referencewavelength 390 nm as needed) Run Time 32 minutesSiliaChrom® dt C₁₈ is a reverse-phase C₁₈ silica gel medium partiallyendcapped with trimethylsilyl groups and polar surface groups (diol),having a purity of the spherical silica gel is at 99.999%. This phasehas no measurable metal content to avoid secondary interactions withbasic or ion species.

TABLE 5 Stability results for orange formulation 40 mg/mL suspensionlong-term conditions (5° C.) Test Lot-044 Stability Interval (Months)Formulation of Example 4 Initial 1 3 6 9 12 18 24 Assay (% label claim)101.2 99.5 100.2 100.8 98.4 100.8 102.0 99.9 Individual Impurities (%)RRT 1.05 0.08 0.09 0.09 0.09 0.09 0.09 0.09 0.09 RRT 1.38-1.40 0.27 0.270.28 0.27 0.27 0.27 0.28 0.27 Total Impurities (%) 0.35 0.36 0.37 0.360.36 0.36 0.37 0.36 pH (direct) 5.0 4.8 5.0 4.9 4.9 5.0 5.0 5.00 TestLot-143 Stability Interval (Months) Formulation of Example 3 Initial 1 36 9 12 Assay (% label claim) 98.2 98.1 99.4 99.4 100.1 99.6 IndividualImpurities (%) RRT 1.05 0.16 0.16 0.15 0.16 0.15 0.16 RRT 1.27-1.28 0.140.13 0.13 0.14 0.14 0.13 RRT 1.38-1.40 0.25 0.25 0.25 0.25 0.24 0.24Total Impurities (%) 0.55 0.54 0.53 0.55 0.53 0.53 pH (direct) 5.0 5.05.0 4.9 5.0 5.0 Viscosity (cP) >499.9 NT >499.9 >499.9 NT >499.9 TestLot-155 Stability Interval (Months) Formulation of Example 3 Initial 1 36 9 12 Assay (% label claim) 99.2 100.4 99.7 97.9 100.2 99.9 IndividualRRT 1.05 0.16 0.16 0.16 0.15 0.15 0.14 Impurities (%) RRT 1.27-1.28 0.130.14 0.13 0.13 0.13 0.14 RRT 1.38-1.40 0.24 0.25 0.24 0.24 0.24 0.25Total Impurities (%) 0.53 0.55 0.53 0.52 0.52 0.53 pH (direct) 5.0 5.04.9 5.0 5.0 5.0 Viscosity (cP) >499.9 NT >499.9 >499.9 NT >499.9 TestLot-142 Stability Interval (Months) Formulation of Example 3 Initial 1 36 9 12 Assay (% label claim) 99.5 99.8 100.0 98.8 99.3 98.5 IndividualImpurities (%) RRT 1.05 0.15 0.15 0.15 0.16 0.16 0.15 RRT 1.27-1.28 0.140.13 0.13 0.14 0.13 0.12 RRT 1.38-1.40 0.25 0.25 0.25 0.25 0.24 0.23Total Impurities (%) 0.54 0.53 0.53 0.55 0.53 0.50 pH (direct) 5.0 5.05.0 5.0 5.0 5.0 Viscosity (cP) 489.4 NT >499.9 >499.9 NT >499.9

TABLE 6 Stability results for orange formulation 40 mg/mL suspensionlong-term conditions (25° C./60% RH) Test Lot-044 Stability Interval(Months) Formulation of Example 4 Initial 1 3 6 12 Assay (% label claim)101.2 102.0 102.8 102.8 102.3 Individual Impurities (%) RRT 1.05 0.080.09 0.09 0.09 0.09 RRT 1.38-1.40 0.27 0.27 0.28 0.27 0.27 TotalImpurities (%) 0.35 0.36 0.37 0.36 0.36 pH (direct) 5.0 4.9 5.0 4.9 5.0Test Lot-143 Stability Interval (Months) Formulation of Example 3Initial 1 3 6 12 Assay (% label claim) 98.2 99.3 99.6 99.7 100.3Individual Impurities (%) RRT 1.05 0.16 0.16 0.16 0.16 0.16 RRT1.27-1.28 0.14 0.13 0.14 0.14 0.13 RRT 1.38-1.40 0.25 0.25 0.25 0.240.24 Total Impurities (%) 0.55 0.54 0.55 0.54 0.53 pH (direct) 5.0 5.05.0 4.9 5.0 Viscosity (cP) >499.9 NT >499.9 >499.9 >499.9 Test Lot-155Stability Interval (Months) Formulation of Example 3 Initial 1 3 6 12Assay (% label claim) 99.2 100.2 99.5 99.7 101.2 Individual Impurities(%) RRT 1.05 0.16 0.16 0.16 0.15 0.14 RRT 1.27-1.28 0.13 0.13 0.13 0.130.14 RRT 1.38-1.40 0.24 0.25 0.24 0.24 0.25 Total Impurities (%) 0.530.54 0.53 0.52 0.53 pH (direct) 5.0 5.0 4.9 5.0 5.0 Viscosity(cP) >499.9 NT >499.9 >499.9 >499.9 Test Lot-142 Stability Interval(Months) Formulation of Example 3 Initial 1 3 6 12 Assay (% label claim)99.5 99.4 99.7 105.7 99.4 Individual Impurities (%) RRT 1.05 0.15 0.150.14 0.16 0.15 RRT 1.27-1.28 0.14 0.13 0.13 0.13 0.13 RRT 1.38-1.40 0.250.25 0.25 0.26 0.23 Total Impurities (%) 0.54 0.53 0.52 0.55 0.51 pH(direct) 5.0 4.9 5.0 4.9 5.0 Viscosity (cP) 489.4 NT >499.9 >499.9>499.9

Example 6—Further Aqueous Oral Pharmaceutical Suspension CompositionComprising Vamorolone

Oral pharmaceutical compositions were prepared as a suspension byblending the ingredients in the amounts listed below at Table 7 to forma suspension.

TABLE 7 4% Vamorolone formulations (wt. %) Ingredient 1.3 2.2 2.3 3.1Vamorolone 4.0 4.0 4.0 Dextrose Anhydrous, USP 1.0 — — 1.0 Sucralose —0.1 0.1 — Sodium Carboxymethyl 0.045 (high — — 0.50 cellulose visc.)Xanthan Gum, NF — 0.3 0.3 0.15 Avicel CL591 1.2 — — 1.2 Microcrystallinecellulose Sodium Phosphate 0.28 0.28 0.28 0.19 Dibasic, anhydrous CitricAcid 0.21 0.21 0.21 0.19 Monohydrate Methylparaben — — — 0.10 SodiumBenzoate 0.5 0.5 0.20-0.10 0.20 Potassium sorbate 0.2 0.2 — — SodiumEDTA 0.1 0.1 — — Glycerin 5.0 5.0 5.0 5.0 Orange flavor 0.1 0.1 0.1 0.158.4108.UL PHA Sterile Purified Qs to Qs to Qs to Qs to Water, USP 100100 100 100 pH 4.0 4.0 4.0 5.0 Viscosity (cP) 598 424 — —

Other uses of the disclosed methods will become apparent to those in theart based upon, inter alia, a review of this patent document.

What is claimed is:
 1. An aqueous oral pharmaceutical suspensioncomposition comprising: vamorolone Form I; at least one suspendingagent; and at least one suspension vehicle.
 2. The suspension of claim1, comprising vamorolone Form I in an amount of between about 2% andabout 10% w/w.
 3. The suspension of claim 2, comprising vamorolone FormI in an amount of about 4% w/w.
 4. The suspension of claim 1, whereinthe suspending agent is chosen from acacia, agar, alginic acid or a saltthereof, bentonite, carbomers, carboxymethylcellulose or a salt thereof,carrageenan, corn starch, ethylcellulose, gelatin, guar gum,hydroxyethylcellulose, hydroxyethylmethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,microcrystalline cellulose, pectin, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, colloidal silicon dioxide, tragacanth,xanthan gum, and mixtures thereof.
 5. The suspension of claim 4, whereinthe suspending agent is chosen from carboxymethylcellulose or a saltthereof, microcrystalline cellulose, xanthan gum, and mixtures thereof.6. The suspension of claim 4, wherein the suspending agent comprises amixture of microcrystalline cellulose, xanthan gum, andcarboxymethylcellulose, or a salt thereof.
 7. The suspension of claim 4,wherein the suspending agent comprises a mixture of microcrystallinecellulose, xanthan gum, and sodium carboxymethylcellulose.
 8. Thesuspension of claim 1, wherein the at least one suspending agent ispresent in an amount of between about 0.5% to about 5% w/w.
 9. Thesuspension of claim 1, wherein the suspension vehicle is chosen fromxylitol, propylene glycol, glycerin, sorbitol, liquid glucose, dextrose,and mixtures thereof.
 10. The suspension of claim 9, wherein thesuspension vehicle is propylene glycol, dextrose, or a mixture thereof.11. The suspension of claim 1, wherein the suspension vehicle is presentin an amount of from about 3% to about 10% w/w.
 12. The suspension ofclaim 11, wherein the suspension vehicle comprises glycerin, thesuspension agent comprises xanthan gum, and vamorolone Form I in anamount of about 4% w/w.
 13. The suspension of claim 1, whereinvamorolone Form I is further characterized by an X-ray powderdiffraction pattern comprising peaks, in terms of ° 2θ, at about 11.9,about 13.7, about 16.1, and about 18.3 with radiation Cu Kα.
 14. Thesuspension of claim 1, wherein vamorolone Form I is furthercharacterized by an X-ray powder diffraction pattern substantially asshown in FIG.
 1. 15. The suspension of claim 1, wherein vamorolone FormI is further characterized by an exothermic event onset at 180.7° C. anda melting event with an onset and peak temperatures of 231.0° C. and234.7° C., respectively, as measured by differential scanningcalorimetry.
 16. The suspension of claim 15, wherein vamorolone Form Iis further characterized by a differential scanning calorimetry tracesubstantially as shown in FIG.
 3. 17. The suspension of claim 1, whereinvamorolone Form I is further characterized by a thermogravimetricanalysis profile showing less than about 0.5% weight loss below about175° C.
 18. The suspension of claim 17, wherein vamorolone Form I isfurther characterized by a thermogravimetric analysis profilesubstantially as shown in FIG.
 2. 19. The suspension of claim 1, whereinthe vamorolone Form I has a chemical purity of at least about 95%, atleast about 96%, at least about 97%, at least about 98%, at least about99%, or at least about 99.5% by high performance liquid chromatography.20. The suspension of claim 1, wherein the suspension has total chemicalimpurities of not more than about 0.6% by high performance liquidchromatography.
 21. The suspension of claim 1, wherein the suspensionhas not more than about 0.5% by high performance liquid chromatographyof an epoxide having the formula:


22. A crystalline form of vamorolone characterized by one or more of thefollowing: (a) an X-ray powder diffraction pattern comprising two ormore peaks, in terms of ° 2θ, at about 11.9, about 13.7, about 16.1, andabout 18.3 with radiation Cu Kα; (b) an X-ray powder diffraction patternsubstantially as shown in FIG. 1; (c) a thermogravimetric analysisprofile showing less than about 0.5% weight loss below about 175° C.;(d) a thermogravimetric analysis profile substantially as shown in FIG.2; (e) an exothermic event onset at 180.7° C. and a melting event withan onset and peak temperatures of 231.0° C. and 234.7° C., respectively,as measured by differential scanning calorimetry; and (f) a differentialscanning calorimetry trace substantially as shown in FIG. 3, wherein thecrystalline form has a chemical purity of at least about 95% by highthroughput liquid chromatography.
 23. The crystalline form of claim 22,having a chemical purity of at least about 96%, at least about 97%, atleast about 98%, at least about 99%, or at least about 99.5% by highperformance liquid chromatography.
 24. A crystalline form of vamorolonecharacterized by one or more of the following: (g) an X-ray powderdiffraction pattern comprising two or more peaks, in terms of ° 2θ, atabout 11.9, about 13.7, about 16.1, and about 18.3 with radiation Cu Kα;(h) an X-ray powder diffraction pattern substantially as shown in FIG.1; (i) a thermogravimetric analysis profile showing less than about 0.5%weight loss below about 175° C.; (j) a thermogravimetric analysisprofile substantially as shown in FIG. 2; (k) an exothermic event onsetat 180.7° C. and a melting event with an onset and peak temperatures of231.0° C. and 234.7° C., respectively, as measured by differentialscanning calorimetry; and (l) a differential scanning calorimetry tracesubstantially as shown in FIG. 3, wherein the crystalline form has aparticle size such that d90 is less than about 50 μm.
 25. An oralpharmaceutical composition comprising the crystalline form of vamoroloneof claim
 24. 26. An oral pharmaceutical composition comprising thecrystalline form of vamorolone of claim 22.